Pharmaceutical compositions may advantageously be administered by inhalation to or through the lung of a patient. In inhalation therapy, a pharmaceutical delivery device, such as a dry powder inhaler (“DPI”), is typically employed to deliver a prescribed dose of a pharmaceutical composition and, hence, medicament to the pulmonary system of a patient. As is well known in the art, in a typical DPI, a dose of the pharmaceutical composition is positioned in an aerosolization chamber, where it is aerosolized and, hence, dispersed into respirable particles by airflow supplied by a pressurized source of gas or by the patient's inspiration effort. It is also well known in the art that in order to settle in the appropriate regions of the lung associated with local and/or systemic drug delivery, the dispersed particles must be of suitable size.
The pulmonary system includes the upper airways, including the oropharynx and larynx, followed by the lower airways, which include the trachea followed by bifurcations into bronchi and bronchioli. The upper and lower airways are called the conducting airways. The terminal bronchioli then divide into respiratory bronchioli, which then lead to the alveolar region, or the deep lung. See, Gonda, I, “Aerosols for Delivery of Therapeutic and Diagnostic Agents to the Respiratory Tract”, Critical Reviews in Therapeutic Drug Carrier Systems, vol. 6, pp. 273-313 (1990).
The smooth muscle regions of the conducting airways, and particularly the lower airways, possess receptors (i.e., protein based, macromolecular complexes existing within cell membranes which, upon interaction with specific agents, change conformation and lead to the triggering of a cellular response, such as smooth muscle cell contraction or relaxation) that are the primary target site of local medicament particle delivery. The alveolar region of the deep lung, although it too may possess receptors effecting local response, is the target site for pulmonary systemic delivery, as the alveoli provide access to vascular system through a closely associated vascular capillary network.
It is well known that medicament particles deposit in specific areas of the pulmonary system based upon the aerodynamic size of the particles and the flow rate of the fluid within which they are entrained. Typically, with average inhalation flow rates of between 10 and 60 liters per minute, particles having an aerodynamic diameter in the range of 0.5 to 3 μm are suitable for systemic delivery, as these particles deposit selectively in the deep lung. Particles having an aerodynamic diameter in the range of approximately 0.5 to 10 μm, preferably, 1 to 6 μm, and more preferably, 3 to 6 μm are suitable for local lung delivery, as they will deposit in the conductive airways.
Particles having an aerodynamic diameter greater than 10 μm generally deposit in the mouth, throat or upper airways, offering little therapeutic benefit. Particles having an aerodynamic diameter less than 0.5 μm do not settle out of the air flow to deposit in the lungs, and are subsequently respired when the patient exhales.
The effectiveness of dry powder pharmaceutical composition delivery depends upon the ability to precisely and reproducibly meter small quantities of medicament into doses. The metering is typically achieved by diluting the medicament in a pharmaceutical composition containing one or more excipients. The pharmaceutical composition can then be metered with a greater margin of error than a highly potent medicament alone.
The pharmaceutical composition should be sufficiently flowable to permit the composition to be poured or otherwise transferred into individual doses. Measures of flowability are typically quantified by the compressibility of the powder composition, as well as its “angle of repose.” Measurement of these features may be made using standardized methodologies known in the art.
Compositions are also advantageously highly aerosolizable, to clear the composition from the inhaler device. The composition is preferably dispersible into particles of respirable size. Measurements of aerosolizibility and dispersiblity may be made by measuring the emitted dose and fine particle fraction of the composition, respectively, using methodologies known to the art. A common device used in measuring fine particle fraction is an Anderson Cascade Impactor.
Efforts in the area of meterability have long included the use of excipients, such as milled or micronized lactose, to dilute the medicament in the pharmaceutical composition, allowing microgram quantities of very potent medicaments to be precisely metered into milligram sized doses with an acceptable degree of control. By controlling the size ranges of the excipient powders, gains have been reported in flowability, dispersability and aerosolization of dry powder medicament formulations.
For example, in EP 0,663,815 an excipient powder is disclosed for use with an inhalable micronized medicament that has coarse and fine excipient fractions. The coarse fraction improves aerosolibility (i.e., emitted dose), while the fine fraction improves dispersability (i.e., measured as fine particle fraction). The coarse excipient fraction (i.e., mill ground) has an average particle size of at least 20 μm. The fine excipient fraction has an average particle size no greater than 10 μm. Similarly, the medicament has a particle size no greater than 10 μm.
In PCT Publication WO 00/33789 an excipient powder is disclosed comprising a coarse first fraction of which at least 80% by weight has a particle size of at least 10 μm; a fine second fraction which at least 90% by weight has a particle size of no greater than 10 μm; and a third fraction consisting of a ternary agent. Preferably, the ternary agent is provided in an additional fine (i.e., 10 μm or less) fraction, but slightly larger sizes are acceptable. The disclosed suitable ternary agents include water soluble and physiologically acceptable materials, i.e., water surface active or amino acids, peptides and polypeptides or derivatives thereof, with the preferred ternary agent being L-leucine. According to WO 00/33789, particles with a diameter in the range of 10 to 30 μm have an adverse effect on powder flow characteristics without imparting any benefit of medicament delivery (i.e., dispersion).
In an effort to increase the aerodynamic properties (aerosolizibility and dispersability) of the particles delivered to the selected target region of the lungs, recent efforts have led to a departure from the use of medicament particles milled to respirable size and then blended with excipient carriers. The new approach appears to be the use of respirable engineered particle compositions have morphologies and physical and chemical attributes with allegedly superior aerodynamic characteristics. These particles may be hollow or porous, and have a range of particle densities, all providing better aerosolization characteristics.
For example, according to WO 99/16419, prior art compositions containing milled respirable drug particles and large excipient carrier particle systems may allow for at least some medicament particles to loosely bind to the surface of the large carrier surface and disengage upon inhalation, but a substantial amount of the medicament fails to disengage from the large lactose particles and is deposited in the throat. To allow undesirable throat deposition to be reduced, PCT Patent Publication WO 99/16419 discloses microporous microparticles containing a medicament, an excipient (i.e., lactose) and surfactant. The microporous nature of these particles purportedly provides superior aerodynamic characteristics, allowing particle-to-particle aggregation to be overcome without the use of large excipient particles. This advance allows the large excipient carriers particles to be eliminated from the formulation altogether.
Similar to the microporous microparticles disclosed in WO 99/16419, U.S. Pat. No. 5,993,805 discloses smooth, spherical, solid walled, hollow microparticles (1 to 10 μm in size) that are intended for aerosolized medicament delivery to the lung(s). This reference similarly does not address the use of large excipient particles.
U.S. Pat. Nos. 5,874,064, 5,855,913 and 5,985,309, which are incorporated by reference herein, disclose low density particle compositions that can be readily entrained into the inhalation path of a patient and deposited into the desired areas of the lungs of a patient to effectuate local or systemic delivery. The particle compositions have a tap density less than 0.4 g/cm3 and a mass mean diameter in the range of 5 to 30 μm to yield an aerodynamic diameter of 1 to 5 μm. The medicament is adsorbed, absorbed, or otherwise incorporated onto or into the matrix of low-density particles. Advantageously, but optionally, these low-density particles are deliverable with larger carrier particles having no medicament, but a mean diameter in the range of 50 to 100 μm. No other mention is made of attributes of the large carrier particles in question.
Progress in the art of dry powder pharmaceutical compositions, in terms of meterability, flowability, dispersiblity and aerosolibility remains desirable. Micronized medicament/excipient blends are encumbered to a certain degree by their inherent aerodynamic attributes. Thus, achieving very high degrees of aerosolibility and dispersiblity using micronized excipients is somewhat limited by these attributes.
Modification of the physical structure of the particles incorporating the medicament or bioactive agent via particle engineering is also often difficult or impossible due to the physical and chemical properties of the active agent itself. Indeed, it is well known that not all medicaments (or bioactive agents) can be incorporated in a particle matrix to provide desired aerodynamic properties suitable for inhalation. Limitations also exist in the ability to incorporate specific concentrations, such as very high or low concentrations, of certain medicaments into suitable matrix forms.
Thus, there exists a need to provide a pharmaceutical composition suitable for delivery of medicaments that have a high degree of aerosolibility and dispersability. There also exists a need for a pharmaceutical composition that does not depend on the capability of a medicament to be able to form a medicament-excipient matrix, which matrix is delivered to the target sites in the lung to be released for local and/or systemic delivery. Additionally, there exists a need to provide pharmaceutical compositions with increased stability, whereby the aerosolization and dispersion characteristics of the composition can be maintained throughout a given shelf life without giving an inconsistent therapeutic or delivery profile.
It is therefore an object of the present invention to provide a novel dry powder pharmaceutical composition having improved meterability, flowability, dispersability and/or aerosolibility.
It is another object of the present invention to provide a dry powder pharmaceutical composition including excipient particles having one or more of such improved properties.
It is another object of the present invention to provide a pharmaceutical composition that is not dependent on a given medicament's ability to be formed into a matrix particle of medicament and excipient.
It is yet another object of the present invention to provide pharmaceutical compositions having improved physical and/or chemical stability.